Insulin-like growth factors and cancer

Abstract

The insulin-like growth factors (IGFs). also known as somatomedins, have been identified as a result of three separate lines of research carried out over the last 30 years (Van Wyk & Underwood, 1978). First, IGFs promote incorporation of 35-sulphate into cartilage, hence 'sulphation' factor (Salmon & Daughaday, 1957). Secondly, they mediate the mitogenic activity of serum (Pierson & Temin, 1972) and medium conditioned by rat hepatocytes (multiplication stimulating activity, MSA; Dulak & Temin. 1973). Thirdy. IGFs have insulin-like activity which is not inhibited by anti-insulin antibodies (non-suppressive insulin-like activity, NSILA: Froesch et al., 1963). Sequence analysis revealed that these functions are subserved by two main peptide: IGF-I, also known as somatomedin-C (Klapper et al.. 1983) and IGF-II. of which the rat form is MSA (Rinderknecht & Humbel. 1978; Marquardt et al.. 1981). The IGF terminology is now preferred as there is no somatomedin designation for IGF-II (Daughaday et al.. 1987). IGF-I (70 residues, MW 7649) and IGF-II (67 residues. MW 7471) are single chain peptides with around 70% sequence homology, and 50% homology with pro-insulin. Mature IGFs have A and B domains where the homology with proinsulin is highest, a C-peptide domain which has no sequence homology with proinsulin. and a carboxyterminal D domain (Daughaday & Rotwein. 1989). The IGF-I gene is located on chromosome 12q, and the IGF-II gene is on chromosome llp, contiguous with the insulin gene (Barreca & Minuto. 1989). In the mouse, the IGF-II gene is imprinted. that is. there is a difference in expression between the maternal and paternal genes. Specifically, it is the paternal IGF-II gene which is active (Willison. 1991). IGF-I is synthesised by the liver and also by other viscera including kidney and lung (D'Ercole et al., 1984). Hepatic synthesis, which largely determines serum levels, is regulated by growth hormone (GH) and also varies with liver function and nutritional status (Underwood et al., 1986; Zapf & Froesch. 1986). In endocrine-sensitive tissues. IGF-I gene expression may be regulated by hormones other than GH. Notably in rat uterus, IGF-I expression is enhanced by oestrogen, and is repressed to a small extent by GH (Murphy & Friesen, 1988). In vitro, IGF-I is a potent mitogen for normal cells including chondrocytes and other mesenchymal derivatives (Clemmons & Van Wyk, 1981). In vivo, IGF-I has acute insulin-like anabolic effects on adipose tissue, muscle and liver (Zapf & Froesch, 1986; Guler et al.. 1987). However its most important physiological role is as the primary regulator of growth, especially of mesenchymal tissues including bone and cartilage (Schoenle et al., 1982; Van Buul-Offers et al.. 1986; Mathews et al., 1988). IGF-II has metabolic and mitogenic effects experimentally, but its physiological function is unclear. Serum concentrations are less dependent on GH. and it causes less growth promotion in hypophysectomised animals (Schoenle et al., 1983). IGF-II mRNA is expressed in foetal tissues of mesenchymal origin, including kidney, liver